Substituted 1H-pyridinyl-2-ones as GABAA-α 2/3 ligands

ABSTRACT

Substituted 1H-Pyridinyl-2-ones are useful as GABA A -Alpha 2/3 ligands.

This application is a 371 of PCT/aB 98/01593, filed Jun. 1, 1998.

The present invention relates to a class of substituted1H-pyridinyl-2-one derivatives and to their use in therapy. Moreparticularly, this invention is concerned with substituted1H-pyridinyl-2-one derivatives which are ligands for GABA_(A) receptorsand are therefore useful in the therapy of deleterious mental states.

Receptors for the major inhibitory neurotransmitter, gamma-aminobutyricacid (GABA), are divided into two main classes: (1) GABA_(A) receptors,which are members of the ligand-gated ion channel superfamily; and (2)GABA_(B) receptors, which may be members of the G-protein linkedreceptor superfamily. Since the first cDNAs encoding individual GABA_(A)receptor subunits were cloned the number of known members of themammalian family has grown to thirteen (six α subunits, three βsubunits, three γ subunits and one δ subunit). It may be that furthersubunits remain to be discovered; however, none has been reported since1993.

Although knowledge of the diversity of the GABA_(A) receptor gene familyrepresents a huge step forward in our understanding of this ligand-gatedion channel, insight into the extent of subtype diversity is still at anearly stage. It has been indicated that an α subunit, a β subunit and aγ subunit constitute the minimum requirement for forming a fullyfunctional GABA_(A) receptor expressed by transiently transfecting cDNAsinto cells. As indicated above, a δ subunit also exists, but is presentonly to a minor extent in GABA_(A) receptor populations.

Studies of receptor size and visualisation by electron microscopyconclude that, like other members of the ligand-gated ion channelfamily, the native GABA_(A) receptor exists in pentameric form. Theselection of at least one α, one β and one γ subunit from a repertoireof thirteen allows for the possible existence of more than 10,000pentameric subunit combinations. Moreover, this calculation overlooksthe additional permutations that would be possible if the arrangement ofsubunits around the ion channel had no constraints (i.e. there could be120 possible variants for a receptor composed of five differentsubunits).

Receptor subtype assemblies which do exist include, amongst many others,α1β2γ2, α2β2/3γ2, α3βγ2/3, α2βγ1, α5β3γ2/3, α6βγ2, α6βδ and α4βδ.Subtype assemblies containing an α1 subunit are present in most areas ofthe brain and are thought to account for over 40% of GABA_(A) receptorsin the rat. Subtype assemblies containing α2 and α3 subunitsrespectively are thought to account for about 25% and 17% of GABA_(A)receptors in the rat. Subtype assemblies containing an α5 subunit areexpressed predominantly in the hippocampus and cortex and are thought torepresent about 4% of GABA_(A) receptors in the rat.

A characteristic property of all known GABA_(A) receptors is thepresence of a number of modulatory sites, one of which is thebenzodiazepine (BZ) binding site. The BZ binding site is the mostexplored of the GABA_(A) receptor modulatory sites, and is the sitethrough which anxiolytic drugs such as diazepam and temazepam exerttheir effect. Before the cloning of the GABA_(A) receptor gene family,the benzodiazepine binding site was historically subdivided into twosubtypes, BZ1 and BZ2, on the basis of radioligand binding studies. TheBZ1 subtype has been shown to be pharmacologically equivalent to aGABA_(A) receptor comprising the α1 subunit in combination with a βsubunit and γ2. This is the most abundant GABA_(A) receptor subtype, andis believed to represent almost half of all GABA_(A) receptors in thebrain.

Two other major populations are the α2βγ2 and α3βγ2/3 subtypes. Togetherthese constitute approximately a further 35% of the total GABA_(A)receptor repertoire. Pharmacologically this combination appears to beequivalent to the BZ2 subtype as defined previously by radioligandbinding, although the BZ2 subtype may also include certain α5-containingsubtype assemblies. The physiological role of these subtypes hashitherto been unclear because no sufficiently selective agonists orantagonists were known.

It is now believed that agents acting as BZ agonists at α1βγ2, α2βγ2 orα3βγ2 subunits will possess desirable anxiolytic properties. Theα1-selective GABA_(A) receptor agonists alpidem and zolpidem areclinically prescribed as hypnotic agents, suggesting that at least someof the sedation associated with known anxiolytic drugs which act at theBZ1 binding site is mediated through GABA_(A) receptors containing theα1 subunit. Accordingly, it is considered that GABA_(A) receptoragonists which bind more effectively to the α2 and/or α3 subunit than toα1 will be effective in the treatment of anxiety with a reducedpropensity to cause sedation. Also, agents which are antagonists orinverse agonists at α1 might be employed to reverse sedation or hypnosiscaused by α1 agonists.

The compounds of the present invention, being selective ligands forGABA_(A) receptors, are therefore of use in the treatment and/orprevention of a variety of disorders of the central nervous system. Suchdisorders include anxiety disorders, such as panic disorder with orwithout agoraphobia, agoraphobia without history of panic disorder,animal and other phobias including social phobias, obsessive-compulsivedisorder, stress disorders including post-traumatic and acute stressdisorder, and generalized or substance-induced anxiety disorder;neuroses; convulsions; migraine; and depressive or bipolar disorders,for example single-episode or recurrent major depressive disorder,dysthymic disorder, bipolar I and bipolar II manic disorders, andcyclothymic disorder.

The present invention provides a compound which is a derivative offormula I or a salt or prodrug thereof:

wherein:

R is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₂₋₆alkenyloxy or C₂₋₆ alkynyloxy, and when R is not hydrogen, R isoptionally independently substituted by one or more halogen atoms orhydroxy, cyano or amino groups;

V is CH or N;

W is O or S;

X is phenyl unsubstituted or substituted with one or more groupsindependently selected from C₁₋₆ alkyl, CF₃, cyano, nitro, halogen,amino, C₁₋₆ alkoxy, C₁₋₆ alkylcarbonyloxy or C₁₋₆ alkylcarbonylamino; asix-membered heteroaromatic group containing one or two nitrogen atomsor a five-membered heteroaromatic group containing one, two, three orfour heteroatoms independently selected from N, O and S providing thatnot more than one heteroatom is selected from O and S, theheteroaromatic group being unsubstituted or substituted with one or moregroups independently selected from halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₄₋₆ cycloalkenyl and CF₃;

Y is hydrogen, NR¹R², C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, Ar,O(CH₂)_(n)Ar¹, (CH₂)_(j)Ar², C_(k)H_(2k-2)Ar², C_(k)H_(2k-4)Ar² orNH(CH₂)_(l)Ar⁵;

R¹ and R² are independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ hydroxyalkyl and (CH₂)_(m)Ar³;

Ar is thienyl, furyl or a six-membered heteroaromatic ring containingone or two nitrogen atoms which is unsubstituted or substituted with oneor more groups independently selected from halogen and C₁₋₆ alkyl groupsand which is optionally fused to a benzene ring; or naphthyl or phenylrings which rings are unsubstituted or substituted with one or moregroups independently selected from halogen, cyano, amino, nitro, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CF₃, CF₃O, C₁₋₆ alkoxy, C₂₋₆alkenyloxy, C₂₋₆ alkynyloxy, C₁₋₆ alkylthio, C₂₋₆ alkenylthio, C₂₋₆alkynylthio, hydroxy, hydroxyC₁₋₆alkyl, NR³R⁴, OC(O)NR³R⁴, C₁₋₆alkoxyphenylC₁₋₆alkoxy, cyanoC₁₋₆alkyl, cyanoC₂₋₆alkenyl,cyanoC₂₋₆alkynyl, pyridyl, phenyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl, C₁₋₆ alkoxycarbonylC₂₋₆alkenyl, C₁₋₆alkoxycarbonylC₂₋₆alkynyl and —O(CH₂)_(p)O— and which is optionallyfused to a benzene ring;

Ar¹, Ar², Ar³ and Ar⁵ are independently selected from pyridyl; andphenyl which is unsubstituted or substituted with one or more groupsindependently selected from halogen, cyano, amino, nitro, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, CF₃, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₂₋₆alkynyloxy, C₁₋₆ alkylthio, C₂₋₆ alkenylthio, C₂₋₆ alkynylthio and—O(CH₂)_(p)O—;

Z is halogen, C₃₋₆ cycloalkyl, C₁₋₆ alkylthio, C₂₋₆ alkenylthio, C₂₋₆alkynylthio, NR⁵R⁶, Ar⁴ or Het¹;

R³, R⁴, R⁵ and R⁶ are independently as defined for R¹ and R²;

Ar⁴ is phenyl which is unsubstituted or substituted with one or moregroups independently selected from halogen, cyano, amino, nitro, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CF₃, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy,C₂₋₆ alkynyloxy, C₁₋₆ alkylthio, C₂₋₆ alkenylthio, C₂₋₆ alkynylthio and—O(CH₂)_(p)O—;

Het¹ is a four- or five-membered saturated ring containing a nitrogenatom optionally substituted by a hydroxy group; a six-membered saturatedring containing a nitrogen atom, and optionally a further nitrogen atomor an oxygen atom; an unsaturated five-membered heterocyclic groupcontaining one, two, three or four heteroatoms independently selectedfrom N, O and S providing that not more than one heteroatom is selectedfrom O and S; or an unsaturated six-membered heterocyclic groupcontaining one or two nitrogen atoms; each of which moieties isunsubstituted or substituted by one or more groups independentlyselected from halogen, cyano, amino, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, CF₃, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy and C₂₋₆ alkynyloxy;

j is 1, 2, 3 or 4;

k is 2, 3 or 4;

l is 1, 2, 3 or 4;

m and n are independently 0, 1, 2, 3 or 4; and

p is 1, 2 or 3.

R is preferably hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₂₋₆ alkenyloxy or C₂₋₆ alkynyloxy, in particular hydrogen, C₁₋₄alkyl or C₂₋₄ alkenyl. When R is not hydrogen, R may be unsubstituted orsubstituted by one or two, preferably one, substituent independentlyselected from halogen, preferably fluorine or chlorine, especiallyfluorine, and hydroxy. In particular R can be hydrogen, methyl,n-propyl, ethenyl, prop-1-en-3-yl, hydroxyethyl or fluoroethyl.

V is generally CH. V may be N.

W is generally O. W may be S.

When X is phenyl it is preferably unsubstituted or substituted with C₁₋₆alkyl, CF₃, cyano, nitro, halogen, amino, C₁₋₆ alkoxy, C₁₋₆alkylcarbonyloxy or C₁₋₆ alkylcarbonylamino, for example, C₁₋₆ alkyl,amino, halogen or C₁₋₆ alkylcarbonylamino, more preferably unsubstitutedor substituted with C₁₋₆ alkylcarbonylamino and most preferablyunsubstituted or substituted with methylcarbonylamino.

When X is phenyl it may be unsubstituted. When X is phenyl it may beunsubstituted or substituted by fluorine, amino or methylcarbonylamino.

When X is a heteroaromatic group it is preferably unsubstituted orsubstituted with halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆cycloalkyl, C₄₋₆ cycloalkenyl or CF₃, more preferably unsubstituted orsubstituted with C₁₋₆ alkyl or C₃₋₆ cycloalkyl, most preferablyunsubstituted or substituted with methyl or cyclopropyl. When X is aheteroaromatic group it may be unsubstituted or substituted by methyl,isopropyl, cyclopropyl, ethyl or chlorine.

When X is a heteroaromatic group it is preferably pyridyl orfive-membered, in particular, an isothiazole, thiazole, pyrazolyl,thiadiazole oxadiazole, pyridine or thiophene, most preferably anisothiazol-5-yl group optionally substituted at the 3-position, athiazol-2-yl group optionally substituted at the 4-position, apyrazol-3-yl group optionally substituted at the 1-position, athiadiazol-3-yl group, in particular 1,2,4-thiadiazol-3-yl group,optionally substituted at the 5-position, an oxadiazol-3-yl group, inparticular a 1,2,4-oxadiazol-3-yl group, optionally substituted at the5-position, a pyridin-2-yl group, a thien-2-yl group optionallysubstituted at the 4-position, a thien-3-yl group.

Y is preferably hydrogen, NR¹R², C₂₋₆ alkynyl, Ar, O(CH₂)_(n)Ar¹ orC_(k)H_(2k-4)Ar².

R¹ and R² are preferably independently selected from C₁₋₆ alkyl and(CH₂)_(m)Ar³ and most preferably from methyl and (CH₂)_(m)Ar³.

When Ar is thienyl or furyl, thienyl is preferred, it is preferablyunsubstituted or substituted with halogen or C₁₋₆ alkyl and optionallyfused to a benzene ring and most preferably unsubstituted or fused to abenzene ring.

When Ar is a six-membered heteroaromatic ring it is preferably pyridylor pyrimidinyl, and it is unsubstituted or substituted with halogen orC₁₋₆ alkyl and most preferably unsubstituted.

When Ar is naphthyl it is preferably unsubstituted and when phenyl it ispreferably unsubstituted or substituted with R^(x) and/or R^(y) and/orR^(z) wherein R^(x) and R^(y) are independently chosen from halogen,cyano, amino, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CF₃, OCF₃,C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₂₋₆ alkynyloxy, C₁₋₆ alkylthio, C₂₋₆alkenylthio, C₂₋₆ alkynylthio, hydroxy, hydroxyC₁₋₆alkyl, NR³R⁴,OC(O)NR³R⁴, C₁₋₆ alkoxyphenylC₁₋₆alkoxy, cyanoC₁₋₆alkyl,cyanoC₂₋₆alkenyl, cyanoC₂₋₆alkynyl, pyridyl, phenyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkoxycarbonylC₁₋₆alkyl, C₁₋₆alkoxycarbonylC₂₋₆alkenyl, C₁₋₆ alkoxycarbonylC₂₋₆alkynyl and—O(CH₂)_(p)O— and R^(z) is halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy and Ar isoptionally fused to a benzene ring. More preferably, R^(x) and R^(Y) areindependently chosen from halogen, C₁₋₆ alkoxy, —O(CH₂)_(p)O—,hydroxyC₁₋₆alkyl, C₁₋₆ alkylthio, C₁₋₆ alkoxyphenylC₁₋₆alkoxy, NR³R⁴,OC(O)NR³R⁴, cyanoC₂₋₆alkenyl, pyridyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkoxycarbonylC₂₋₆alkenyl, phenyl and OCF₃. Most preferably, when Ar isphenyl, it is unsubstituted and optionally fused to a benzene ring orsubstituted with one, two or three groups independently chosen fromfluorine, chlorine, bromine, methoxy and methyl, or with —O(CH₂)_(p)O—,hydroxymethyl, ethoxy, isopropoxy, methoxyphenylmethoxy, NR³R⁴,O(CO)NR³R⁴, cyanoethenyl, pyridyl, ethoxycarbonyl,ethoxycarbonylethenyl, methylthio, phenyl, ethyl or CF₃O.

Ar¹, Ar², Ar³ and Ar⁵ are independently preferably pyridyl; or phenylwhich is unsubstituted or substituted with halogen, cyano, amino, nitro,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CF₃, C₁₋₆ alkoxy, C₂₋₆alkenyloxy, C₂₋₆ alkynyloxy, C₁₋₆ alkylthio, C₂₋₆ alkenylthio, C₂₋₆alkynylthio or —O(CH₂)_(p)O—. More preferably when any of Ar¹, Ar², Ar³and Ar⁵ are phenyl the one that is phenyl is unsubstituted orsubstituted with methyl.

Ar⁴ is preferably phenyl which is unsubstituted or substituted withhalogen, cyano, amino, nitro, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,CF₃, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₂₋₆ alkynyloxy, C₁₋₆ alkylthio, C₂₋₆alkenylthio, C₂₋₆ alkynylthio or —O(CH₂)_(p)O— and most preferablyunsubstituted phenyl.

Z is preferably chloro, C₃₋₆ cycloalkyl, C₁₋₆ alkylthio, NR⁵R⁶, Ar⁴ orHet¹ and most preferably chloro, C₃₋₅ cycloalkyl, methylthio, NR⁵R⁶, Ar⁴or Het^(1.)

When Het¹ is a saturated ring it is preferably unsubstituted orsubstituted with halogen, cyano, amino, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, CF₃, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy or C₂₋₆ alkynyloxy; morepreferably it is a derivative of piperidine, thiomorpholine, azetidine,pyrrolidine or morpholine which derivative is preferably unsubstitutedand which is preferably attached to the rest of the molecule via anitrogen ring atom. When Het¹ is a derivative of pyrrolidine it may beunsubstituted or substituted by a hydroxy group.

When Het¹ is an unsaturated group it is preferably unsubstituted orsubstituted with halogen, cyano, amino, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, CF₃, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy or C₂₋₆ alkynyloxy, morepreferably it is unsubstituted or substituted with C₁₋₆ alkyl and mostpreferably it is unsubstituted or substituted with methyl. Preferablywhen Het¹ is an unsaturated group it is a derivative of furan,thiophene, imidazole, pyridine, pyrazine, pyrimidine or pyridazine. WhenHet¹ is furan it is preferably unsubstituted or substituted with C₁₋₆alkyl, more preferably it is unsubstituted or substituted with methyl.When Het¹ is an unsaturated group it may be unsubstituted.

R³ and R⁴ are preferably independently C₁₋₆ alkyl and most preferablyare both methyl.

R⁵ and R⁶ are preferably independently chosen from hydrogen and C₂₋₆alkynyl, more preferably from hydrogen and propenyl and most preferablyone is hydrogen and the other is propenyl.

j is preferably 1 or 2.

k is preferably 2.

l is preferably 1.

m and n are preferably 1.

p is preferably 1 or 2 and most preferably 2.

As used herein, the expression “C₁₋₆ alkyl” includes methyl and ethylgroups, and straight-chained or branched propyl, butyl, pentyl and hexylgroups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyland tert-butyl. Derived expressions such as “C₁₋₆ alkoxy” and “C₁₋₄alkyl” are to be construed accordingly.

The expression “C₂₋₆ alkenyl” includes ethenyl and straight-chained orbranched propenyl, butenyl, pentenyl and hexenyl groups. Particularalkenyl groups are ethenyl, n-propenyl, isopropenyl and butenyl. Derivedexpressions such as “C₂₋₄ alkenyl” and “C₁₋₆ alkenyloxy” are to beconstrued accordingly.

The expression “C₂₋₆ alkynyl” includes ethynyl and propynyl groups andstraight-chained or branched butynyl, pentynyl and hexynyl groups.Particular alkynyl groups are ethynyl, propynyl, butynyl and isobutynyl.Derived expressions such as “C₁₋₆ alkynyloxy” are to be construedaccordingly.

Typical C₃₋₆ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. Derived expressions such as “C₃₋₅cycloalkyl” are to be construed in an analogous manner.

The expressions “five-membered heteroaromatic group” and “unsaturatedfive-membered heterocyclic group” as used herein include furyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and thiadiazolyl groups.

The expression “six-membered heteroaromatic ring” as used hereinincludes pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl groups.

The expression “unsaturated six-membered heterocyclic group” as usedherein includes pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl andtriazinyl groups.

The term “halogen” as used herein includes fluorine, chlorine, bromineand iodine, especially fluorine or chlorine.

For use in medicine, the salts of the compounds of formula I will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example, be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include alkali metal salts, e.g. sodium orpotassium salts; alkaline earth metal salts, e.g. calcium or magnesiumsalts; and salts formed with suitable organic ligands, e.g. quaternaryammonium salts.

The present invention includes within its scope prodrugs of thecompounds of formula I above. In general, such prodrugs will befunctional derivatives of the compounds of formula I which are readilyconvertible in vivo into the required compound of formula I.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. It is to beunderstood that all such isomers and mixtures thereof in any proportionare encompassed within the scope of the present invention.

The compounds of the present invention possess desirable bindingproperties at various GABA_(A) receptor subtypes. The compounds inaccordance with the present invention have good affinity as ligands forthe α2 and/or α3 subunit of the human GABA_(A) receptor. Typically, thecompounds of this invention display more effective binding to the α2and/or α3 subunit than to the α1 subunit. Typically, the compounds ofthe present invention have a binding affinity (K_(i)) for the subunit of100 nM or less.

Specific compounds within the scope of the invention include:

3-(4-methoxyphenyl)-1-methyl-5-(thiazol-2-yl)-1H-[2,4′]bipyridinyl-6-one;

5-(4-methoxyphenyl)-1-methyl-6-(5-methylfuran-2-yl)-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-1H-pyridin-2-one;

3-(4-methoxyphenyl)-1-methyl-5-(4-methylthiazol-2-yl)-1H-[2,4′]bipyridinyl-6-one;

5-(4-methoxyphenyl)-1-methyl-3-(thiazol-2-yl)-6-(3-thienyl)-1H-pyridin-2-one;

5-(4-methoxyphenyl)-1-methyl-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-6-(3-thienyl)-1H-pyridin-2-one;

5-(4-methoxyphenyl)-1-methyl-6-(5-methylfuran-2-yl)-3-(thiazol-2-yl)-1H-pyridin-2-one;

3-(4-methoxyphenyl)-1-methyl-5-(thiophen-2-yl)-1H-[2,4′]bipyridinyl-6-one;

3-(4-methoxyphenyl)-1-methyl-5-(4-cyclopropylthiazol-2-yl)-1H-[2,4′]bipyridinyl-6-one;

1-methyl-3-(4-pyridyl)- 5-(thiazol-2-yl)-1H-[2,4′]bipyridinyl-6-one;

3-(4-methoxyphenyl)-1-methyl-5-(4-methylthiophen-2-yl)-1H-[2,4′]bipyridinyl-6-one;

5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-pyridazin-4-yl-1H-pyridin-2-one;

1-methyl-3-(4-methylthiazol-2-yl)-6-(pyridazin-4-yl)-5-(2,4,6-trifluorophenyl)-1H-pyridin-2-one;

5-benzyloxy-1-methyl-3-(4-methylthiazol-2-yl)-6-(pyridin-4-yl)-1H-pyridin-2-one;

5-benzyloxy-1-methyl-3-(4-methylthiazol-2-yl)-6-phenyl-1H-pyridin-2-one;

1-methyl-3-(1-methylpyrazol-3-yl)-5-(4-methoxyphenyl)-6-(pyridin-4-yl)-1H-pyridin-2-one;

5,6-diphenyl-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one;

5-(3,4-methylenedioxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-(pyridin-4-yl)-1H-pyridin-2-one;

5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-(pyrazin-2-yl)-1H-pyridin-2-one;

5-(4-methoxyphenyl)-6-(4-pyridyl)-3-phenyl-1-methyl-1H-pyridin-2-one;

5-(4-methoxyphenyl)-3-(3-methylisothiazol-5-yl)-6-(4-pyridyl)-1-methyl-1H-pyridin-2-one;

1-methyl-3-(4-methylthiazol-2-yl)-5-(N-methyl-N-benzylamino)-6-(4-pyridyl)-1H-pyridin-2-one;

1-methyl-3,5-diphenyl-6-(4-pyridyl)-1H-pyrazin-2-one;

5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-(4-morpholino)-1H-pyridin-2-one;

6-dimethylamino-5-(4-Methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one;

1-methyl-3-(4-methylthiazol-2-yl)-6-(4-morpholino)-1H-[3,4′]bipyridin-2-one;

1-methyl-3-(4-methylthiazol-2-yl)-6-(1-pyrrolidino)-1H-[3,4′]bipyridin-2-one;

and salts and prodrugs thereof.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention and a pharmaceutically acceptablecarrier. Preferably these compositions are in unit dosage forms such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, auto-injector devices or suppositories; for oral, parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. For preparing solid compositions such astablets, the principal active ingredient is mixed with a pharmaceuticalcarrier, e.g. conventional tableting ingredients such as corn starch,lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate,dicalcium phosphate or gums, and other pharmaceutical diluents, e.g.water, to form a solid preformulation composition containing ahomogeneous mixture of a compound of the present invention, or apharmaceutically acceptable salt thereof. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from 0.1 to about 500 mg of the activeingredient of the present invention. Typical unit dosage forms containfrom 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of theactive ingredient. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of anxiety, a suitable dosage level is about 0.01 to250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, andespecially about 0.05 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

The present invention also provides a compound of formula I for use in amethod of treatment of the human or animal body, in particular for usein the treatment of anxiety.

The present invention further provides the use of a compound of formulaI for the manufacture of a medicament for the treatment of disorders forwhich the administration of a ligand for the GABA_(A) receptor α2 and/orα3 subunits is required, for example, for the treatment of anxiety.

There is also disclosed a prophylactic or therapeutic method oftreatment of a subject suffering from a condition for which theadministration of a ligand for the GABA_(A) receptor α2 and/or α3subunit is required, which comprises administering to that subject aprophylactically or therapeutically effective amount of a compound offormula I. An example of such a condition is anxiety.

The present invention also provides a process for producing a compoundof formula I in which V is CH which comprises:

(a) Reacting a compound of formula II with a compound of formula III

wherein Y is as defined above, G is Z, or when Z is a nucleophile, Goptionally represents a leaving group such as methoxy, R′ is a leavinggroup such as C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl which isunsubstituted or substituted with one or more halogen atoms and istypically C₁₋₆ alkyl such as methyl or tertiary butyl and J is hydroxyor a halogen atom, preferably hydroxyl, to give a compound of formulaIV:

wherein G, R′ and Y are as defined above.

The compound of formula II is typically activated before reaction, forexample, by reacting with N, N-carbonydiimidazole in a suitable solventsuch as dry tetrahydrofuran. The compound of formula III is optionallyconverted into its enolate before reaction by reacting with a strongbase such as lithium diisopropylamide in a suitable solvent such as drytetrahydrofuran optionally with cooling, typically to −78° C.

Activated compound II is typically reacted without purification as isthe compound of formula III when activated.

When the compound of formula III is activated, reaction with thecompound of formula II is typically carried out with cooling generallyto −780° C. When the compound of formula III is not activated it istypically reacted with the compound of formula II with cooling,generally to −30° C., and with a strong base, such as sodium hydride;the reaction mixture is generally stirred for about one hour and thenallowed to warm gradually to room temperature typically for about eighthours.

(b) Converting the compound of formula IV into a compound of formula V:

wherein G and Y are as defined above, which is achieved typically atroom temperature or with heating, for example to 150° C., for from 2 to18 hours, in a solvent such as dimethyl sulfoxide, generally in thepresence of a salt such as sodium chloride and water; or in the presenceof an acid such as trifluoracetic acid.

Alternatively, a compound of formula (V) in which Y is NR¹R², G is Z andR¹ and R² are as defined above, can be obtained by reacting a compoundof formula HNR¹R² with a compound of formula XIX:

wherein Z is as defined above and L⁷ is a leaving group such as ahalogen, e.g. bromine, typically in the form of the hydrohalide. Thereaction is typically carried out in a solvent such as dichloromethaneat about room temperature for about 18 hours.

(c) Reacting the compound of formula V with a compound of formula VI:

wherein R″ and R′″ are independently hydrogen or C₁₋₆ alkyl, such asmethyl, and L¹ and L² are leaving groups such as C₁₋₆ alkoxy, typicallymethoxy, to give a compound of formula VII:

wherein G, R″, R′″ and Y are as defined above.

The reaction is typically carried out in a solvent such asdimethylformamide at room temperature or at an elevated temperature suchas 80° C. for from 3 to 20 hours.

(d) Reacting the compound of formula VII with a compound of formulaVIII:

wherein X and R are as defined above, to give a compound of formula I′:

wherein R, X and Y are as defined above and when G was Z, G′ is Z andwhen G was a leaving group, G′ is hydroxy, i.e. when G′ is Z thecompound of formula I′ is a compound of formula I in which V is CH.

The reaction is typically carried out under an inert atmosphere, such asnitrogen, in the presence of a small quantity of a protic solvent suchas methanol, with a strong base, such as sodium hydride, in a solventsuch as tetrahydrofuran or dimethylformamide, at from room temperatureto 50° C. for from 15 to 20 hours.

(e) When G¹ is OH, reacting with halogenating agent such as POCl₃ toobtain a compound of formula I″:

wherein R, X and Y are as defined above and G″ is halogen, for examplechlorine. This reaction is generally carried out under reflux under aninert atmosphere such as nitrogen for about one and a half hours.

(f) Reacting the compound of formula I″ with a compound of formula Z—H,wherein Z is as defined above, generally in a solvent such as DMSO,typically at about 100° C. for about 18 hours, to obtain a compound offormula I in which Z is a nucleophile and V is CH.

In an alternative process, a compound of formula I in which V is CH isproduced by a process comprising:

(a) Reacting a compound of formula V with a compound of formula IX:

NHR  (IX)

 to give a compound of formula X:

 wherein R, Y and Z are as defined above.

The reaction is typically carried out in a solvent such as chloroform,under an inert atmosphere, such as nitrogen, with cooling, for exampleto 0° C., with a catalyst, such as titanium tetrachloride, for from 5 to10 hours.

(b) Reacting the compound of formula X with a compound of formula XI:

 wherein L⁴ is a leaving group such as chlorine and P is a protectinggroup such as benzyl, to give a compound of formula XII:

wherein P, L⁵, R, Y and Z are as defined above.

The reaction is typically carried out in a solvent, such as drytetrahydrofuran, at a reduced temperature, such as −78° C., under aninert atmosphere such as nitrogen followed by warming, typically to 0°C., for from 1 to 3 hours.

(c) Reacting the compound of formula XII in a Vilsmeier reaction,typically using POCl₃ and dimethylformamide, to give a compound offormula XIII:

 wherein R, P, Y and Z are as defined above.

The reaction is generally carried out by adding POCl₃ to the compound offormula XII at about room temperature and allowing the reaction toproceed for about an hour. DMF is then generally added, typically withcooling to about 0° C. following by heating to about 75° C. for about 90minutes. This is typically followed by further cooling to about 0° C.and the addition of further dimethylformamide followed by heating toabout 75° C. for about 3 hours.

(d) Deprotecting the compound of formula XIII to obtain a compound offormula XIV:

 wherein R, Y and Z are as defined above, typically by reacting in atransfer dehydrogenation reaction, for example using palladium oncarbon, in the presence of a hydrogen source such as ammonium formate,an acid such as glacial acetic acid and in a solvent such as methanolfor about 3.5 hours at about room temperature.

(e) Converting the hydroxy group in the compound of formula XIV into aleaving group by reaction with an acid derivative of formula XV:

L⁶—K  (XV)

 wherein K is an acyl or sulfonyl group, such as SO₂CF₃, and L⁶ is aleaving group such as OSO₂CF₃, to give a compound of formula XVI:

 wherein K, R, Y and Z are as defined above.

The reaction is generally carried out in a solvent such as drydichloromethane in the presence of a base such as pyridine generallywith cooling to about −78° C. and for about one hour.

(f) Reacting the compound of formula XVI with a compound of XVII:

X—B(OH)₂  (XVII)

 wherein X is as defined above, to obtain a compound of formula I. Thereaction is carried out in the presence of a transition metal catalystsuch as Pd(PPh₃)₄ generally under an inert atmosphere, such as nitrogen,typically at reflux, for about two hours.

Compounds of formula XVII can be made by reacting a compound of formulaXVIII:

 X—H  (XVIII)

wherein X is as defined above, with a trialkylborate, such astrimethylborate, in the presence of a strong base, such asn-butyllithium, generally at room temperature for about two hours.

Compounds of formula XVIII are commercially available or can be made byknown methods.

Where they are not commercially available, the starting materials offormulae II, III, HNR¹R², XIX, VI, VIII, IX, Z—H, XI and XV may beprepared by standard methods well known from the art.

Compounds of formula I in which W is S can be prepared by reacting theanalagous compound in which W is O with Lawesson's reagent or P₂S₅.

Compounds of formula I in which V is N can be prepared by reacting acompound of formula:

with Z-boronic acid (XX) wherein R, X, Y and Z are as previouslydefined. The compound of formula XX is generally in the form of a salt,such as the lithium salt. The reaction is generally carried out under aninert atmosphere such as nitrogen and in a solvent such as 3:1 ethyleneglycol dimethylether:water. Generally addition of the compound offormula XX to the compound of formula XIX is followed by addition of asalt, such as sodium carbonate, and then a catalyst, such astetrakis-triphenylphosphine palladium. The order in which thesecompounds are combined is not critical. The reaction is generallycarried out at reflux for several hours.

The compound of formula XIX can be prepared by reacting a compound offormula:

with a compound of formula:

Li—R  (XXII)

wherein R, X and Y are as previously defined. The reaction is generallypreceded by addition of a strong base, such as NaH, to the compound offormula XXI generally at 0° C. under an inert atmosphere such asnitrogen in a solvent such as 4:1 ethylene glycoldimethylether:dimethylformamide for about 5 minutes. The reactionbetween the compounds of formulae XXI and XXII is then carried out forseveral hours.

Compounds of formula XXI can be prepared by methods analagous to thatdisclosed in Cheeseman et al., J. Chem. Soc. Chem. Commun. 1971, (18),2977-2979 from known starting materials which are either commerciallyavailable or can be made by standard methods well known in the art.

Compounds of formula XX and XXII are either commercially available orcan be made by standard techniques well known in the art.

Compounds of formula I″ constitute a further feature of the presentinvention as they act as ligands of GABA A receptors containing the α2and/or α3 subunits. Preferred substitution patterns of these compoundsare the same as for the compounds of formula I mutatis mutandis.

It will be understood that any compound of formula I initially obtainedfrom any of the above processes may, where appropriate, subsequently beelaborated into a further compound of formula I by techniques known fromthe art.

Where the above-described processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The novel compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The novel compounds may, for example, beresolved into their component enantiomers by standard techniques such aspreparative HPLC, or the formation of diastereomeric pairs by saltformation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The novel compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

EXAMPLE 13-(4-Methoxyphenyl)-1-methyl-5-(thiazol-2-yl)-1H-[2,4′]bipyridinyl-6-one

Step1: N,N-Carbonyldiimidazole (20.3 g) was added portionwise to astirred suspension of isonicotinic acid (15.4 g) in dry tetrahydrofuran(200 cm³). The gently effervescent mixture was stirred at roomtemperature for 90 minutes, forming an orange solution. A solution oflithium diisopropylamide was prepared by the addition of n-butyllithium(2.5 M, hexanes; 100 cm³) to a stirred solution of diisopropylamine (35cm³) in dry tetrahydrofuran (250 cm³) at 0° C. under nitrogen. Thesolution was cooled to −78° C. for 15 minutes, followed by the dropwiseaddition of a solution of methyl 2-(4-methoxyphenyl)acetate (45 g) indry tetrahydrofuran (50 cm³) at −78° C. The yellow enolate solution wasstirred at —78° C. for 20 minutes, followed by addition of theimidazolide solution dropwise via cannula. After stirring at −78° C. for45 minutes the bright yellow suspension was warmed to room temperature.The mixture was poured into aqueous hydrochloric acid (1.3 M; 700 cm³)and washed with hexane (200 cm³). The aqueous solution was basified topH 3 with aqueous sodium hydroxide (4 M) and then to pH 7 with saturatedaqueous sodium hydrogencarbonate. The neutralised solution was extractedwith dichloromethane (2×400 cm³). The organic extracts were washed withbrine (300 cm³), dried (magnesium sulphate), filtered and concentratedto give a brown oil that crystallised on standing. The material wastriturated with ethyl acetate-diethyl ether (1:1; 50 cm³) and filteredto give 2-(4-methoxyphenyl)-3-oxo-3-(pyridin-4-yl)propionic acid methylester as an off-white solid (14.7 g; 42%). δ_(H) (250 MHz; CDCl₃) 3.77(3 H, s, OCH₃), 3.79 (3 H, s, OCH₃), 5.48 (1 H, s, MeO₂CCH), 6.90 (2 H,d, J 9, methoxyphenyl H-2), 7.28 (2 H, d, J 9, methoxyphenyl H-3), 7.70(2 H, d, J 6, pyridyl H-3) and 8.77 (2 H, d, J 6, pyridyl H-2).

Step 2: A mixture of 2-(4-methoxyphenyl)-3-oxo-3-(pyridin-4-yl)propionicacid methyl ester (14.7 g), sodium chloride (6.0 g) and water (1.9 cm³)in dimethyl sulphoxide (200 cm³) was stirred at 150° C. for 2 hours. Thesolution was cooled to room temperature, poured into water (600 cm³) andextracted with ethyl acetate-diethyl ether (1:1; 2×400 cm³). Theextracts were dried (magnesium sulphate), filtered and concentrated togive 2-(4-methoxyphenyl)-1-(pyridin-4-yl)ethanone as a brown solid (10.2g; 87%). δ_(H) (250 MHz; CDCl₃) 3.79 (3 H, s, OCH₃), 4.44 [2 H, s,C(O)CH₂Ar], 6.88 (2 H, d, J 9, methoxyphenyl H-2), 7.16 (2 H, d, J 9,methoxyphenyl H-3), 7.77 (2 H, d, J 6, pyridyl H-3) and 8.80 (2 H, d, J6, pyridyl H-2).

Step 3: A solution of 2-(4-methoxyphenyl)-1-(pyridin-4-yl)ethanone (10.2g) and dimethylformamide-dimethylacetal (20 cm³) in drydimethylformamide (50 cm³) was stirred at 80° C. for 4 hours. Themixture was cooled, poured into water (500 cm³) and extracted with ethylacetate (3×200 cm³). The combined extracts were washed with brine (100cm³), dried (magnesium sulphate), filtered and concentrated to give ayellow solid. The material was washed well with diethyl ether-hexane(1:9; 2×100 cm³) and dried in vacuo to give3-dimethylamino-2-(4-methoxyphenyl)-1-(pyridin-4-yl)propen-1-one as abeige solid (7.7 g; 60%). δ_(H) (250 MHz; CDCl₃) 2.78 [6 H, broad s,N(CH₃)₂], 3.79 (3 H, s, OCH₃), 6.79 (2 H, d, J 9, methoxyphenyl H-2),7.04 (2 H, d, J 9, methoxyphenyl H-3), 7.24 (2 H, d, J 6, pyridyl H-3)7.40 (1 H, s, C═CH) and 8.51 (2 H, d, J 6, pyridyl H-2).

Step 4: A solution of3-dimethylamino-2-(4-methoxyphenyl)-1-(pyridin-4-yl)propen-1-one (2.53g), N-methyl thiazol-2-ylacetamide (1.70 g) and methanol (0.73 cm³) indry dimethylformamide (20 cm³) was added via cannula at room temperatureto a stirred suspension of sodium hydride (55% in oil; 0.80 g) in drydimethylformamide (10 cm³) under nitrogen. The mixture was stirred at40° C. for 18 hours, then poured into water (200 cm³). The resultingyellow precipitate was collected and recrystallised from ethyl acetateto give3-(4-methoxyphenyl)-1-methyl-5-(thiazol-2-yl)-1H-[2,4′]bipyridinyl-6-oneas a yellow powder (2.18 g; 62%) m.p. 224-225° C. (EtOAc). Found: C,66.9; H, 4.45; N, 11.2. C₂₁H₁₇N₃O₂S requires C, 67.2; H, 4.6; N, 11.2%.δ_(H) (360 MHz; CDCl₃) 3.50 (3 H, s, NCH₃), 3.74 (3 H, s, OCH₃), 6.70 (2H, d, J 9, methoxyphenyl H-2), 6.93 (2 H, d, J 9, methoxyphenyl H-3),7.15 (2 H, d, J 6, pyridyl H-3), 7.50 (1 H, d, J 3, thiazolyl H-5), 7.96(1 H, d, J 3, thiazolyl H-4), 8.64 (2 H, d, J 6, pyridyl H-2) and 8.72(1 H, s, pyridone H-4); m/z (ESP+) 376 (MH⁺; 100%).

EXAMPLE 25-(4-Methoxyphenyl)-1-methyl-6-(5-methylfuran-2-yl)-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-1H-pyridin-2-one

Preparation of this compound was carried out as described for Example 1replacing isonicotinic acid with 5-methylfuran-2-carboxylic acid in Step1 and N-methyl-thiazol-2-ylacetamide with N-methyl3-methyl[1.2.4]oxadiazol-5-ylacetamide in Step 4. Yellow solid m.p. 179°C.; (Found: C, 67.03; H, 5.06; N, 10.87. C₂₁H₁₉N₃O₄ requires C, 66.83;H, 5.07; N, 11.13%); δ_(H) (360 MHz; CDCl₃) 2.33 (3 H, s, furan-Me),2.48 (3 H, s, oxadiazole-Me), 3.57 (3 H, s, NMe), 3.79 (3 H, s, OMe),5.96 (1 H, d, J 4, furan4-H), 6.02 (1 H, d, J 4, furan H-3), 6.80 (2 H,d, J 9, ArH o to OMe), 6.97 (2 H, d, J 9, ArH m to OMe), 8.35 (1 H, s,pyridone H-4); m/z (ES)378 (MH⁺, 100%).

EXAMPLE 33-(4-Methoxyphenyl)-1-methyl-5-(4-methylthiazol-2-yl)-1H-[2,4′]bipyridinyl-6-one

Preparation of this compound was carried out as described for Example 1replacing N-methyl thiazol-2-ylacetamide with N-methyl4-methylthiazol-2-ylacetamide in Step 4. Lemon yellow prisms m.p.228-230° C. (EtOAc). Found: C, 68.1; H, 4.7; N, 10.7. C₂₂H₁₉N₃O₂Srequires C, 67.9; H, 4.9; N, 10.8%. δ_(H) (360 MHz; CDCl₃) 2.58 (3 H, s,ArCH₃), 3.48 (3 H, s, NCH₃), 3.74 (3 H, s, OCH₃), 6.70 (2 H, d, J 9,methoxyphenyl H-2), 6.95 (2 H, d, J 9, methoxyphenyl H-3), 7.08 (1 H, s,thiazolyl H-5), 7.15 (2 H, d, J 6, pyridyl H-3) 8.65 (2 H, d, J 6,pyridyl H-2) and 8.90 (1 H, broad s, pyridone H-4); m/z (ESP+) 390 (MH⁺;100%).

EXAMPLE 45-(4-Methoxyphenyl)-1-methyl-3-(thiazol-2-yl)-6-(3-thienyl)-1H-pyridin-2-one

Preparation of this compound was carried out as described for Example 1replacing isonicotinic acid with thiophene-3-carboxylic acid in Step 1.Yellow needles m.p. 185-187° C. (EtOAc/hexanes)(Found: C, 63.38; H,3.99; N, 7.54. C₂₀H₁₆N₂O₂S₂ requires C, 63.14; H, 4.24; N, 7.36%); δ_(H)(360 MHz, d₆-DMSO) 3.42 (3 H, s, NMe), 3.71 (3 H, s, OMe), 6.79 (2 H, d,J 9, methoxyphenyl H-2), 7.02 (2 H, d, J 9, methoxyphenyl H-3), 7.54 (1H, dd, J 1 and 4, thiophene-H), 7.55 (1 H, dd, J 1 and 3, thiophene-H),7.64 (1 H, dd, J 3 and 4, thiophene-H), 7.77 (1 H, d, J 3.3,thiazole-H), 7.95 (1 H, d, J 3.3, thiazole-H), 8.47 (1 H, s, pyridoneH-4); m/z (ESP+) 381 (MH⁺).

EXAMPLE 55-(4-Methoxyphenyl)-1-methyl-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-6-(3-thienyl)-1H-pyridin-2-one

Preparation of this compound was carried out as described for Example 1replacing isonicotinic acid with thiophene-3-carboxylic acid in Step 1and N-methyl thiazol-2-ylacetamide with N-methyl5-cyclopropyl[1.2.4]oxadiazol-3-ylacetamide in Step 4. Yellow needlesm.p. 171-173° C. (EtOAc/hexanes)(Found: C, 65.33; H, 4.42; N, 10.37.C₂₂H₁₉N₅O₃S requires C, 65.17; H, 4.72; N, 10.36%); δ_(H) (360 MHz,d₆-DMSO) 1.1-1.2 (2 H, m, CH₂), 1.2-1.3 (2 H, m, CH₂), 2.3-2.4 (1 H, m,cyclopropyl-H), 3.26 (3 H, s, NMe), 3.70 (3 H, s, OMe), 6.79 (2 H, d, J9, methoxyphenyl H-2), 7.06 (2 H, d, J 9, methoxyphenyl H-3), 7.10 (1 H,dd, J 3 and 4, thiophene-H), 7.28 (1 H, dd, J 1 and 3, thiophene-H),7.70 (1 H, dd, J 1 and 4, thiophene-H), 8.07 (1 H, s, pyridone H-4); m/z(ESP+) 406 (MH⁺).

EXAMPLE 65-(4-Methoxyphenyl)-1-methyl-6-(5-methylfuran-2-yl)-3-(thiazol-2-yl)-1H-pyridin-2-one

Preparation of this compound was carried out as described for Example 1replacing isonicotinic acid with 5-methylfuran-2-carboxylic acid inStep 1. Orange rhombs m.p. 205-206° C. (EtOAc/hexanes)(Found: C, 66.95;H, 4.71; N, 7.38. C₂₁H₁₈N₂O₃S requires C, 66.65; H, 4.79; N, 7.40%);δ_(H) (360 MHz, d₆-DMSO) 2.27 (3 H, s, furan-Me), 3.49 (3 H, s, NMe),3.74 (3 H, s, OMe), 6.16 (1 H, d, J 3.2, furan-H), 6.34 (1 H, d, J 3.2furan-H), 6.87 (2 H, d, J 8.8, ArH o to OMe), 7.05 (2 H, d, J 8.8, ArH mto OMe), 7.80 (1 H, d, J 3.2, thiazole-H), 7.98 (1 H, d, J 3.2,thiazole-H), 8.48 (1 H, s, pyridone H-4); m/z (ESP+) 379 (MH⁺).

Example 73-(4-Methoxyphenyl)-1-methyl-5-(thiophen-2-yl)-1H-[2,4′]bipyridinyl-6-one

Preparation of this compound was carried out as described for Example 1replacing N-methyl thiazol-2-ylacetamide with N-methylthien-2-ylacetamide in Step 4. Beige prisms m.p. 213-214° C.(EtOAc)(Found: C, 70.3; H, 5.0; N, 7.5. C₂₂H₁₈N₂O₂S requires C, 70.6; H,4.9; N, 7.5%); δ_(H) (360 MHz; CDCl₃) 3.45 (3 H, s, NCH₃), 3.75 (3 H, s,OCH₃), 6.72 (2 H, d, J 9, methoxyphenyl H-2), 6.91 (2 H, d, J 9,methoxyphenyl H-3), 7.12 (1 H, dd, J 5 and 4, thiophene H-4), 7.17 (2 H,broad m, pyridyl H-3), 7.41 (1 H, dd, J 5 and 1, thiophene H-3), 7.70 (1H, dd, J 4 and 1, thiophene H-5), 7.90 (1 H, s, pyridone H-4) and 8.64(2 H, broad m, pyridyl H-2); m/z (ESP+) 375 (MH⁺; 100%).

EXAMPLE 83-(4-Methoxyphenyl)-1-methyl-5-(4-cyclopropylthiazol-2-yl)-1H-[2,4′]bipyridinyl-6-one

Preparation of this compound was carried out as described for Example 1replacing N-methyl thiazol-2-ylacetamide with N-methyl4-cyclopropylthiazol-2-ylacetamide in Step 4. Bright yellow prisms m.p.211-213° C. (EtOAc)(Found: C, 67.5; H, 5.4; N, 10.1.C₂₄H₂₁N₃O₂S·0.6(H₂O) requires C, 67.6; H, 5.3; N, 9.9%); δ_(H) (360 MHz;CDCl₃) O0.90-1.02 (4 H, m, cyclopropyl CH₂), 2.18-2.24 (1 H, m,cyclopropyl CH), 3.48 (3 H, s, NCH₃), 3.75 (3 H, s, OCH₃), 6.72 (2 H, d,J 9, methoxyphenyl H-2), 6.94 (2 H, d, J 9, methoxyphenyl H-3), 6.98 (1H, s, thiazolyl H-5), 7.16 (2 H, d, J 6, pyridyl H-3), 8.64 (2 H, d, J6, pyridyl H-2) and 8.76 (1 H, broad s, pyridone H-4); m/z (ESP+) 416(MH⁺; 100%).

EXAMPLE 91-Methyl-3-(4-pyridyl)-5-(thiazol-2-yl)-1H-[2,4′]bipyridinyl-6-one

Preparation of this compound was carried out as described for Example 1replacing methyl 2-(4-methoxyphenyl)acetate with methyl 4-pyridylacetatein Step 4. Yellow needles m.p. 251-253° C. (CHCl₃/hexanes)(Found: C,64.85; H, 3.96; N, 15.53. C₁₉H₁₄N₄O₃+0.3 H₂O requires C, 64.88; H, 4.18;N, 15.93%); δ_(H) (360 MHz, d₆-DMSO) 3.37 (3 H, s, NMe), 7.11 (2 H, d, J4.5, pyridyl-H), 7.46 (2 H, d, J 4.5 pyridyl-H), 7.82 (1 H, d, J 3.2,thiazole-H), 8.00 (1 H, d, J 3.2, thiazole-H), 8.41 (2 H, d, J 4.5,pyridyl-H), 8.52 (1 H, s, pyridone H-4), 8.65 (2 H, d, J 4.5,pyridyl-H); m/z (ESP+) 347 (MH⁺).

EXAMPLE 103-(4-Methoxyphenyl)-1-methyl-5-(4-methylthiophen-2-yl)-1H-[2,4′]bipyridinyl-6-one

Preparation of this compound was carried out as described for Example 1replacing N-methyl thiazol-2-ylacetamide with N-methyl4-methylthien-2-ylacetamide in Step 4. Lemon yellow prisms m.p. 169-170°C. (EtOAc). Found: C, 71.4; H, 5.0; N, 7.3. C₂₃H₂₀N₂O₂S requires C,71.1; H, 5.2; N, 7.2%. δ_(H) (360 MHz; CDCl₃) 2.30 (3 H, s, ArCH₃),3.453 (3 H, s, NCH₃), 3.75 (3 H, s, OCH₃), 6.71 (2 H, d, J 9,methoxyphenyl H-2), 6.90 (2 H, d, J 9, methoxyphenyl H-3), 7.00 (1 H, s,thiophene H-3), 7.11 (2 H, d, J 6, pyridyl H-3), 7.56 (1 H, s, thiopheneH-5), 7.85 (1 H, s, pyridone H-4) and 8.60 (2 H, d, J 6, pyridyl H-2);m/z (ESP+) 389 (MH⁺; 100%).

EXAMPLE 115-(4-Methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-pyridazin-4-yl-1H-pyridin-2-one

Preparation of this compound was carried out as described for Example 1replacing isonicotinic acid with pyridazin-4-carboxylic acid in Step 1and N-methyl thiazol-2-ylacetamide with N-methyl4-methylthiazol-2-ylacetamide in Step 4. M.p. 271° C.; (Found: C, 64.86;H, 4.51; N, 14.21. C₂₁H₁₈N₄O₂S requires C, 64.59; H, 4.65; N, 14.35%);δ_(H)(360 MHz; CDCl₃) 2.51 (3 H, s, thiazole-Me), 3.50 (3 H, s, NMe),3.74 (3 H, s, OMe), 6.71 (2 H, d, J 9, methoxyphenyl H-2), 6.89 (2 H, d,J 9, methoxyphenyl H-3), 7.08 (1 H, s, thiazole 5-H), 7.27 (1 H, dd, J 1and 8, pyridazine 5-H), 8.66 (1 H, s, pyridone H-4), 9.06 (1 H, d, J 1,pyridazine 3-H), 9.20 (1 H, dd, J 1 and 8, pyridazine 6-H); m/z 391 (M⁺,100%).

The following compounds were prepared in a similar manner usinganalogous starting materials:

EXAMPLE 121-Methyl-3-(4-methylthiazol-2-yl)-6-(pyridazin-4-yl)-5-(2,4,6-trifluorophenyl)-1H-pyridin-2-one

δ_(H) (250 MHz; CDCl₃); 2.52 (3H, s), 3.50 (3H, s), 6.58 (2H, m), 7.1(1H, s), 7.38 (1H, m), 8.52 (1H, s), 9.1 (1H, s), and 9.28 (1H, dd, J1.2 and 5.3 Hz); m/z (ESP+) 415 (MH⁺).

EXAMPLE 135-Benzyloxy-1-methyl-3-(4-methylthiazol-2-yl)-6-(pyridin-4-yl)-1H-pyridin-2-one

δ_(H) (250 MHz; CDCl₃) 2.56 (3 H, apparent d, J 0.7, thiazole-CH₃), 3.41(3 H, s, CH₃N), 5.05 (2 H, s, PhCH₂O), 6.97 (1 H, d, J 2.4, phenyl),6.99 (1 H, d, J 1.6, phenyl), 7.11-7.07 (3 H, m, aromatic), 7.29-7.20 (3H, aromatic), 8.74-8.72 (3 H, m, pyridone-H and pyridyl-H).

EXAMPLE 145-Benzyloxy-1-Methyl-3-(4-methylthiazol-2-yl)-6-(phenyl)-1H-pyridin-2-one

δ_(H) (360 MHz; CDCl₃) 2.55 (3 H, apparent d, J 0.6, thiazole-CH₃), 3.44(3 H, s, CH₃N), 4.82 (2 H, s, PhC H₂O), 6.96 (1 H, d, J 2.5, phenyl),6.97 (1 H, d, J 1.6, phenyl), 7.03 (1 H, apparent d, J 0.6, thiazole-H),7.25-7.18 (5 H, m, phenyl), 7.50-7.46 (3 H, m, phenyl), 8.72 (1 H, s,pyridone-H).

EXAMPLE 151-Methyl-3-(1-methylpyrazol-3-yl)-5-(4-methoxyphenyl)-6-(pyridin-4-yl)-1H-pyridin-2-one

δ_(H) (360 MHz; CDCl₃) 3.41 (3 H, s, NCH₃), 3.73 (3 H, s, OCH₃), 3.95(3H, s Pyrazole-N-Me), 6.67 (2 H, d, J 9, methoxyphenyl H-2)), 6.90 (2H, d, J 9, methoxyphenyl H-3), 7.11 (2 H, d, J 6, pyridyl H-3), 7.26 (1H, d, J 3, Pyrazole H-4), 7.42 (1 H, d, J 3, Pyrazole H-4), 8.22 (1 H,s, pyridone CH), 8.6 (2 H, d, J 6, pyridyl H-2)

EXAMPLE 165,6-Diphenyl-1-Methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one

δ_(H) (360 MHz; CDCl₃) 2.51 (3 H, s, thiazole-CH₃), 3.50 (3 H, s, CH₃N),7.03-7.01 (3 H, m, phenyl), 7.18-7.12 (5 H, m, phenyl), 7.34-7.32 (3 H,m, phenyl), 8.70 (1 H, s, pyridone-H).

EXAMPLE 175-(3,4-Methylenedioxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-(pyridin-4-yl)-1H-pyridin-2-one

⁶⁷ _(H) (360 MHz; CDCl₃) 2.51 (3 H,s, CH₃), 3.47 (3 H, s, NCH₃), 4.19 (4H, s CH₂CH₂), 6.43 (1 H, dd, J 2, 8, benzodioxan H-5), 6.57 (1 H, d, J2, benzodioxan H-3), 6.63 (1 H, d, J 8, benzodioxan H-6), 7.04 (1 H, s,thiazole H-1), 7.14 (2 H, d, J 6, pyridyl H-3), 8.62 (1 H, s, pyridoneCH), 8.65 (2 H, d, J 6, pyridyl H-2)

EXAMPLE 185-(4-Methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-(pyrazin-2-yl)-1H-pyridin-2-one

Step 1: N,N-Carbonylimidazole (14.86 g) was added to a slurry ofpyrazine-2-carboxylic acid in dry dimethylformamide (100 cm³). Afterstirring for one hour 4-methoxyphenylacetic acid t-butyl ester (10.8 g)was added. The reaction mixture was cooled to −30° C. then sodiumhydride (4.62 g) was added. The reaction mixture was stirred at −30° C.for 1h then allowed to warm to room temperature overnight. The reactionmixture was poured into water and acidified to pH 8 with acetic acid.The solution was extracted with ether (3×250 cm³). The ether extractswere combined, washed with brine, dried over magnesium sulphate filteredand evaporated under reduced pressure to give a solid. The solid waspurified by chromatography using ethyl acetate/hexane (1:1) as eluant.The appropriate fractions were combined and evaporated under reducedpressure to give 2-(4-methoxyphenyl)-3-oxo-3-pyrazine-2-yl propionicacid t-butyl ester as a solid (9.8 g 61%) δ_(H) (250 MHz; CDCl₃) 1.39 (9H, s, C(CH₃)3), 3.70 (3 H, s, OCH₃), 5.87(1 H, s, ^(t)BuO₂CCH), 6.90(2H, d, J 9 Hz, methoxyphenyl H-2) 7.32 (2H, d, J 9 Hz, methoxyphenylH-3) 8.66 (1H, dd pyrazine H-) 8.74 (1H, d pyrazine H-) 9.25 (1H, dpyrazine H-)

Step 2: A mixture of 2-(4-methoxyphenyl)-3-oxo-3-pyrazine-2-yl)propionicacid t-butyl ester (9.7 g) and trifluoroacetic acid (30 cm³) werestirred at room temperature for 18 h. The reaction mixture was pouredonto ice, basified with conc. ammmonia and extracted with ethyl acetate(3×250 ml). The ethyl acetate extracts were combined washed with brinedried over magnesium sulphate, filtered and evaporated under reducedpressure to give a solid. The solid was purified by chromatography usingethyl acetate as eluant. The appropriate fractions were combined andevaporated under reduced pressure to give2-(4-methoxyphenyl)-1-(pyrazin-2-yl)ethanone as a solid (5.1 g 75%)δ_(H) (250 MHz CDCl₃) 3.78 (3H, s, OCH₃), 4.44 (2H, s, C(O)CH₂Ar), 6.84(2H, d, J 9, methoxyphenyl H-2), 7.24 (2H, d, J 9, methoxyphenyl H-3))8.66 (1H, dd pyrazine H-) 8.74 (1H, d pyrazine H-) 9.23 (1H, d pyrazineH-)

Step 3: A solution of 2-(4-methoxyphenyl)-1-(pyrazine-2-yl)ethanone (1.0g) and dimethylformamide-dimethylacetal (10 cm³) were stirred at roomtemperature for 18 h. The excess reagent was evaporated under reducedpressure to give an oil. The oil was dissolved in tetrahydrofuran (60cm³). N-methyl 2-(4-methylthiazol-2-yl)acetamide (0.74 g) and methanol(0.36 cm³) were added followed by sodium hydride (0.42 g). The reactionmixture was stirred at room temperature under nitrogen for 18 h thenpoured into water (500 cm³) and extracted with diethyl ether (3×150cm³). The ether extracts were combined, washed with brine dried overmagnesium sulphate, filtered and evaporated under reduced pressure togive an oil. The oil was purified by chromatography usingdichloromethane (500 cm³), dichloromethane/methanol (99:1, 500 cm³)dichloromethane/methanol (98:2) as eluant. The appropriate fractionswere combined and evaporated under reduced pressure to give a foam,which on tritiation with ether gave a solid. The solid wasrecrystallised from ethyl acetate to give 5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-(pyrazin-2-yl)-1H-pyridin-2-one (0.15 g 8%)as a greenish-yellow solid m.p. 168-170° C. (Found: C, 64.48; H, 4.45;N, 14.22. C21H18N4O2S requires C, 64.60; H, 4.65; N, 14.35%); δ_(H) (360MHz; CDCl₃) 2.52 (3H, s, ArCH₃) 3.53 (3H, s, NMe), 3.74 (3H, s, OCH₃)6.70(2H, d, J 9, methoxyphenyl H-2), 6.92(2H, d, J 9, methoxyphenylH-2), 7.05 (1H, s, thiazolyl H-4) 8.25 (1H, d, J pyrazine H-), 8.52 (1H,d, J pyrazine H-) 8.72 (2H d J pyrazine H- and 1H, s, pyridone H-4); m/z(ESP+) 391 (MH⁺).

EXAMPLE 195-(4-Methoxyphenyl)-6-(4-pyridyl)-3-phenyl-1-methyl-1H-pyridin-2-one

Step 1: A solution of 2-(4-methoxyphenyl)-1-(pyridin-4-yl)ethanone (17.5g), prepared as in Example 1 step 2, in chloroform (200 cm³) wassaturated with methylamine gas at 0° C. The solution was stirred undernitrogen at 0° C. whilst titanium tetrachloride in dichloromethane (1M;40 cm³) was added via syringe. After stirring the brown suspensionovernight at room temperature, anhydrous sodium sulphate (5 g) was addedand the yellow suspension was filtered through celite, washing withdichloromethane. Evaporation of the filtrate gave[(2-(4-methoxyphenyl)-1-pyridin-4-yl)ethylidene]methylamine (16.7 g;90%) as an orange oil; δ_(H) (250 MHz; CDCl₃) 3.48 (3 H, broad s, NCH₃),3.77 (3 H, s, OCH₃), 4.04 (2 H, broad s, ArCH₂), 6.76-6.85 (2 H, m,methoxyphenyl H-2), 6.96-7.05 (2 H, m, methoxyphenyl H-3), 7.26 and 7.58(2 H, 2×d, J 6, pyridyl H-3) and 8.09 (2 H, m, pyridyl H-2).

Step 2: A solution of 2-benzyloxyacetyl chloride (11.7 g) in dry THF (50cm³) was added via cannula to a stirred solution of[(2-(4-methoxyphenyl)-1-pyridin-4-yl)ethylidene]-methylamine (16.7 g) indry THF (150 cm³) at −78° C. under nitrogen. After complete addition thepurple solution was warmed to 0° C. and stirred for 90 minutes. Thebrown suspension was poured into ice/aqueous sodium hydogencarbonate(500 cm³) and extracted with ethyl acetate (2×250 cm³). The extractswere washed with brine (100 cm³), dried (sodium sulphate), filtered andconcentrated to give a black tar. Flash column chromatogaphy on silica,eluting 5 AE 10% methanol-dichloromethane, gave2-benzyloxy-N-[(2-(4-methoxyphenyl)-1-pyridin-4-yl)vinyl]-N-methylacetamide(17.1 g; 64%) as a brown gum; δ_(H) (250 MHz; CDCl₃) 3.16 and 3.24 (3 H,2×s, NCH₃), 3.68 and 3.73 [3 H, 2×s, OCH₂C(O)N], 3.85 (3 H, s, OCH₃),4.36-4.50 (2 H, m, OCH₂Ph), 6.88-7.02 (3 H, m, C=CHAr and methoxyphenylH-2), 7.10-7.40 (9 H, m, methoxyphenyl H-3, pyridyl H-3 and Ph), 8.44and 8.62 (2 H, 2×d, J 6, pyridyl H-2); m/z (ESP+) 389 (MH⁺; 100%).

Step 3: A solution of2-benzyloxy-N-[(2-(4-methoxyphenyl)-1-pyridin-4-yl)vinyl]-N-methylacetamide(7.37 g) in the minimum volume of dichloromethane (10 cm³) was addedslowly at room temperature to stirred phosphorous oxychloride (12 cm³).The brown solution was stirred at room temperature for 1 hour, thencooled to 0° C. before dropwise addition of dimethylformamide (3 cm³).The mixture was stirred at room temperature for 1 hour, then at 75° C.for 90 minutes. The mixture was cooled to 0° C. and furtherdimethylformamide (1.5 cm³) was added dropwise. The mixture was heatedat 75° C. for 3 hours then cooled and poured onto ice (300 cm³). Aqueoussodium hydroxide (2M; 150 cm³) was added with vigorous stirring,followed by additional base to adjust the solution to pH 9-10. Themixture was extractd with dichloromethane (3×100 cm³). The extracts werewashed with water (100 cm³), brine (100 cm³), dried (sodium sulphate),filtered and concentrated. Flash column chromatogaphy on silica, eluting4% methanol-dichloromethane, gave3-(benzyloxy)-5-(4-methoxyphenyl)-6-(4-pyridyl)-1-methyl-1H-pyridin-2-one(2.12 g; 28%) as a brown foam. A sample was recrystallised m.p. 127-130°C. (EtOAc). δ_(H) (360 MHz; CDCl₃) 3.36 (3 H, s, NCH₃), 3.72 (3 H, s,OCH₃), 5.18 (2 H, s, OCH₂Ph), 6.65 (2 H, d, J 9, methoxyphenyl H-2),6.76 (1 H, s, pyridone H-4), 6.78 (2 H, d, J 9, methoxyphenyl H-3), 7.04(2 H, d, J 6, pyridyl H-3), 7.30-7.47 (5 H, m, Ph) and 8.56 (2 H, d, J6, pyridyl H-2); m/z (ESP+) 399 (MH⁺; 100%).

Step 5: 10% Palladium on carbon (0.5 g) was added at room temperature toa stirred solution of3-(benzyloxy)-5-(4-methoxyphenyl)-6-(4-pyridyl)-1-methyl-1H-pyridin-2-one(1.07 g), ammonium formate (1.26 g) and glacial acetic acid (10 cm³) inmethanol (20 cm³). After 3.5 hours the mixture was filtered and thefilter-cake was washed with hydrochloric acid (1M; 150 cm³). Thefiltrate was neutralised with saturated aqueous sodium hydrogencarbonateand extracted with dichloromethane (2×100 cm³). The extracts were dried(sodium sulphate), filtered and concentrated to give3-(4-methoxyphenyl)-6-(4-pyridyl)-3-hydroxy-1-methyl-1H-pyridin-2-one(0.62 g; 75%) as a pale pink solid. A sample was recrystallised m.p.224-226° C. (EtOAc). Found: C, 68.8; H, 5.4; N, 8.6.C₁₈H₁₆N₂O₃.0.1(EtOAc).0.25(H₂O) requires C, 68.7; H, 5.4; N, 8.7%. δ_(H)(360 MHz; CDCl₃) 3.40 (3 H, s, NCH₃), 3.73 (3 H, s, OCH₃), 6.67 (2 H, d,J 9, methoxyphenyl H-2), 6.86 (2 H, d, J 9, methoxyphenyl H-3), 6.90 (1H, broad s, OH), 6.93 (1 H, s, pyridone H-4), 7.06 (2 H, d, J 6, pyridylH-3) and 8.59 (2 H, d, J 6, pyridyl H-2); m/z (ESP+) 309 (MH⁺; 100%).

Step 6: Trifluoromethanesulfonic anhydride (0.60 cm³) was added dropwiseat −78° C. to a stirred suspension of3-(4-methoxyphenyl)-6-(4-pyridyl)-3-hydroxy-1-methyl-1H-pyridin-2-one(0.60 g) and pyridine (0.40 cm³) in dry dichloromethane (30 cm³). Thebrown suspension was briefly warmed to dissolve all material and thenstirred at −78° C. for 1 hour. The mixture was warmed to roomtemperature, poured into saturated aqueous sodium hydrogencarbonate (50cm³) and extracted with dichloromethane (2×30 cm³). The extracts werewashed with water (50 cm³), brine (30 cm³), dried (sodium sulphate),filtered and evaporated to give a brown oil. Trituration with diethylether gave3-trifluoromethanesulfonyl-5-(4-methoxyphenyl)-6-(4-pyridyl)-1-methyl-1H-pyridin-2-one(0.78 g; 90%) as a brown solid. δ_(H) (360 MHz; CDCl₃) 3.39 (3 H, s,NCH₃), 3.74 (3 H, s, OCH₃), 6.70 (2 H, d, J 9, methoxyphenyl H-2), 6.84(2 H, d, J 9, methoxyphenyl H-3), 7.09 (2 H, d, J 7, pyridyl H-3), 7.46(1 H, s, pyridone H-4), and 8.64 (2 H, d, J 7, pyridyl H-2); m/z (ESP+)441 (MH⁺; 100%).

Step 7: A mixture of3-trifluoromethanesulfonyl-5-(4-methoxyphenyl)-6-(4-pyridyl)-1-methyl-1H-pyridin-2-one(0.055 g), benzeneboronic acid (0.25 g) and aqueous sodium carbonate(2M; 2 cm³) in dimethoxyethane (5 cm³) was degassed and purged withnitrogen at room temperature. Tetrakis(triphenylphosphine)palladium (0)(0.1 g) was added and the mixture was refluxed under nitrogen for 2hours. The mixture was diluted with water (10 cm³) and extracted withethyl acetate (3×10 cm³). The extracts were dried (sodium sulphate),filtered and concentrated. Preparative thin layer chromatography,eluting with 95:5 dichloromethane-methanol, gave5-(4-methoxyphenyl)-6-(4-pyridyl)-3-phenyl-1-methyl-1H-pyridin-2-one(0.028 g; 61%) as a pale pink foam. Recrystallised to give a beigepowder m.p. 183-185° C. (EtOAc-hexane). δ_(H) (360 MHz; CDCl₃) 3.39 (3H, s, NCH₃), 3.73 (3 H, s, OCH₃), 6.69 (2 H, d, J 9, methoxyphenyl H-2),6.90 (2 H, d, J 9, methoxyphenyl H-3), 7.13 (2 H, d, J 6, pyridyl H-3),7.35-7.44 (3 H, m, 3 of Ph), 7.59 (1 H, s, pyridone H-4), 7.77 (2 H, d,J 8, 2 of Ph) and 8.60 (2 H, d, J 6, pyridyl H-2); m/z (ESP+) 369 (MH⁺;100%).

EXAMPLE 205-(4-Methoxyphenyl)-3-(3-methylisothiazol-5-yl)-6-(4-pyridyl)-1-methyl-1H-pyridin-2-one

A solution of n-butyllithium in hexanes (1.6 M; 7 cm³) was addeddropwise at −78° C. to a stirred solution of 3-methylisothiazole (1.0 g)in dry tetrahydrofuran (30 cm³) under nitrogen. After stirring theorange suspension for 40 minutes, trimethyl borate (1.35 cm³) was addedand the colourless solution was warmed to room temperature over 2 hours.Water (2.2 cm³) was added and the solution was stirred overnight, thendiluted with diethyl ether (50 cm³) and the off-white precipitatecollected to give hydrated 3-methylisothiazol-5-ylboronic acid (2.1 g).A mixture of the boronic acid (0.35 g),3-trifluoromethanesulfonyl-5-(4-methoxyphenyl)-6-(4-pyridyl)-1-methyl-1H-pyridin-2-one(Example 13 Step 6) (0.35 g), aqueous sodium carbonate (2M; 1 cm³) andtetrakis(triphenylphosphine) palladium (0.1) (0 g) in dimethoxyethane(20 cm³) was degassed and purged with nitrogen at room temperature, thenrefluxed under nitrogen for 1.5 hours. The mixture was cooled, dilutedwith water (40 cm³) and extracted with ethyl acetate (3×20 cm³). Theextracts were dried (magnesium sulphate), filtered and concentrated. Theresulting solid was redissolved in ethyl acetate (20 cm³) and extractedwith dilute hydrochloric acid (1M; 2×30 cm³). The acidic extracts werebasified to pH 10 with aqueous sodium hydroxide (4M) and the resultantwhite precipitate was collected. Preparative thin layer chromatography,eluting 95:5 dichloromethane-methanol, gave5-(4-methoxyphenyl)-3-(3-methylisothiazol-5-yl)-6-(4-pyridyl)-1-methyl-1H-pyridin-2-one(0.028 g; 12%) as a bright yellow solid m.p. 195-198° C. Found: C, 67.5;H, 4.7. C₂₂H₁₉N₃O₂S.0.1 (H₂O) requires C, 67.5; H, 4.95%. δ_(H) (360MHz; CDCl₃) 2.55 (3 H, s, ArCH₃), 3.49 (3 H, s, NCH₃), 3.76 (3 H, s,OCH₃), 6.74 (2 H, d, J 9, methoxyphenyl H-2), 6.90 (2 H, d, J 9,methoxyphenyl H-3), 7.20 (2 H, d, J 6, pyridyl H-3), 7.42 (1 H, s,pyridone H-4), 8.01 (1 H, s, isothiazole H-4) and 8.66 (2 H, d, J 6,pyridyl H-2); m/z (ESP+) 390 (MH⁺; 100%).

EXAMPLE 211-Methyl-3-(4-methylthiazol-2-yl)-5-(N-methyl-N-benzylamino)-6-(4-pyridyl)-1H-pyridin-2-one

Step 1: To a solution of N-benzyl-N-methylamine (3.7 cm³) in drydichloromethane (40 cm³), cooled to 0° C. was added with stirring,4-bromoacetylpyridine hydrobromide (4.0 g). The reaction was allowed towarm to room temperature, then stirred for a further 18 hr. The solventwas stripped at reduced pressure, and the residue partitioned betweenethyl acetate and dilute aqueous Na₂CO₃. The organic phase wasseparated, dried (Na₂SO₄), evaporated, and the residue subjected tochromatography on silica gel, eluent 5% methanol in dichloromethane, toafford 4-(N-benzyl-N-methylaminoacetyl)pyridine, 1.49 g, 43%, as ayellow gum.

Step 2: To a solution of 4-(N-benzyl-N-methylaminoacetyl)pyridine (1.49g, 6.2 mmol) in dry dimethylformamide (10 cm³), was addeddimethylformamide dimethylacetal (10 cm³). The reaction was stirred atroom temperature for 18 hr. The reaction mixture was then diluted withtoluene (25 cm³), and the solvents stripped at reduced pressure. Theresidue was dissolved in dry dimethylformamide (20 cm³), and4-methylthiazole-2-(N-methyl)acetamide (1.05 g), and dry methanol (0.553cm³) added. To this stirred mixture, cooled under an argon atmosphere to0° C. was added with stirring sodium hydride (0.545 g of a 60%dispersion in oil). The reaction was allowed to warm to roomtemperature, then stirred for a further 72 hr. The reaction mixture waspartitioned between ethyl acetate and water. The organic phase wasseparated, dried (Na₂SO₄), evaporated, and the residue subjected tochromatography on silica gel, eluent 2% methanol in dichloromethane, toafford the title compound. Treatment with a solution of hydrogenchloride in methanol afforded the bis-hydrochloride salt, crystallisedfrom hot methanol-dichloromethane-ethyl acetate mixtures, as an orangesolid. Found C, 54.65; H, 5.36; N, 11.05% C₂₃H₂₂NO₁S₁.(HCl)₂.(H₂O)_(1.5)requires C, 54.98; H, 5.42; N, 11.15%). m/e (ES⁺)403 MH⁺.

EXAMPLE 22 1-Methyl-3,5-diphenyl-6-(4-pyridyl)-1H-pyrazin-2-one

Step 1: To a cooled (0° C.) solution of3,5-diphenyl-6-chloro-1H-pyrazin-2-one (1.2 g ; prepared by the methodof Cheeseman et al, J. Chem. Soc. Chem. Comm. 1971, (18), 2977-2979) in4:1 ethylene glycol dimethylether:dimethylformamide (25 cm³)was addedsodium hydride (0.28 g). The reaction was stirred for 5 minutes at 0° C.under nitrogen whereupon lithium bromide (1.17 g) was added. After afurther 5 minutes stirring at room temperature, under nitrogen, methyliodide (4.78 g) was added. The mixture was stirred at room temperatureovernight under nitrogen. The reaction was diluted with water andextracted with ethyl acetate. The organic phase was separated, driedover sodium sulphate and evaporated in vacuo. The residue was subjectedto chromatography on silica gel using ethyl acetate as eluant to afford1-methyl-3,5-diphenyl-6-chloro-1H-pyrazin-2-one as a yellow solid (1.2g; 60%). Found C, 68.98; H, 4.31 ; N, 8.98% C₁₇H₁₃N₂OCl requires C,68.81; H, 4.42; N, 9.44%.m/e (ES⁺) 297/299 (M+H)⁺.

Step 2: To a solution of 1-methyl-3,5-diphenyl-6-chloro-1H-pyrazin-2-one(0.5 g) in 3:1 ethylene glycol dimethylether:water (30 cm³), undernitrogen, was added sequentially 4-pyridyl boronic acid lithium salt(0.42 g), sodium carbonate (0.72 g) and tetrakis-triphenylphosphinepalladium (0.07 g). The reaction was heated at reflux, under nitrogen,overnight. The solvents were evaporated and the residue partitionedbetween water and 5% methanol/dichloromethane. The organic phase wasseparated, dried over magnesium sulphate and evaporated in vacuo. Theresidue was subjected to silica gel chromatography using 2%methanol/dichloromethane as eluant. The product was treated withhydrogen chloride in methanol and recrystallised from ethylacetate/diethyl ether toafford1-methyl-3,5-diphenyl-6-(4-pyridyl)-1H-pyrazin-2-onehydrochloride(0.2 g; 32%) as yellow crystals. Found C, 70.50; H, 4.90;N, 11.20% C₂₂H₁₇N₃O.HCl requires C, 70.30; H, 4.83; N, 11.18%.m/e (ES+)340 (M+H)⁺.

EXAMPLE 235-(4-Methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-(4-morpholino)-1H-pyridin-2-one

Step 1: Methyl 4-methoxyphenylacetate (3.3 g) was dissolved inN,N-dimethylformamide (3 cm³) treated with N,N-dimethylformamidedimethyl acetal (6 cm³) and heated at 100° C. for 18 h. The reaction wasthen cooled and evaporated under high vacuum to afford crudemethyl-3-dimethylamino-2-(4-methoxyphenyl)propenoate (3.6 g) which wasused without further purification. δ_(H) (250 MHz; CDCl₃); 2.68 (6H, s),3.62 (3H, s), 3.8 (3H, s), 6.82 (2H, d, J 8.7 Hz), 7.1 (2H, d, J 8.7 Hz)and 7.54 (1H, s).

Step 2: Methyl-3-dimethylamino-2-(4-methoxyphenyl)propenoate (1.6 g),N-methyl-2-(4-methylthiazol-2-yl)acetamide (1 g) and methanol (0.28 cm³)were dissolved in N,N-dimethylformamide (30 cm³) and cooled to 0° C.under N₂. Sodium hydride (60% suspension in oil, 0.28 g) was added andthe mixture heated at 80° C. for 18 h. The mixture was cooled,partitioned between ethyl acetate (200 cm³) and water (200 cm³). Theaqueous layer was acidified with 2N HCl and extracted with ethyl acetate(3×100 cm³) which was dried (MgSO₄) and evaporated. The crude solid wasrecrystallised from ethyl acetate/ether to yield pure6-hydroxy-5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one(0.3 g). δ_(H) (250 MHz; CDCl₃); 2.37 (3H, s), 3.48 (3H, s), 3.83 (3H,s), 6.37 (1H, s), 6.92 (2H, d, J 8.7 Hz), 7.33 (1H, s) and 7.53 (2H, d,J 8.7 Hz); m/z (ESP+) 329 (MH⁺).

Step 3:6-Hydroxy-5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one(0.13 g) was dissolved in freshly distilled POCl₃ (5 cm³) under N₂ andheated to reflux for 1.5 h. The excess reagent was then removed byevaporation and the residue partitioned between ethyl acetate (100 cm³)and saturated sodium bicarbonate solution (50 cm³). The aqueous layerwas washed with ethyl acetate (2×100 cm³) and the combined organic phasedried (MgSO₄) and evaporated. Purification on silica gel eluting withethyl acetate-hexane mixtures afforded6-chloro-5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-oneas a yellow powder. δ_(H) (250 MHz; CDCl₃); 2.49 (3H, s), 3.86 (3H, s),3.93 (3H, s), 6.96 (2H, d, J 8.7 Hz), 7.01 (1H, s) 7.33 (2H, d, J 8.7Hz) and 8.60 (1H, s).

Step 4:6-Chloro-5-(4-Methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one(0.3 g) was dissolved in DMSO (10 cm³), treated with morpholine (2 cm³)and heated to 100° C. for 18 h. The reaction was then poured intodiethyl ether:ethyl acetate (1:1, 100 cm³) and washed with brine (30cm³). The aqueous phase was extracted with diethyl ether:ethyl acetate(1:1, 2×100 cm³) and the combined organic phase dried (MgSO₄) andevaporated to dryness. The residue was purified on silica gel elutingwith ethyl acetate mixtures to give 0.13 g of5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-(4-morpholino)-1H-pyridin-2-oneas a pale yellow powder. δ_(H) (250 MHz; CDCl₃); 2.48 (3H, s), 2.8 (4H,t, J 4.2 Hz), 3.68 (4H, t, J 4.2 Hz) 3.79 (3H, s), 3.86 (3H, s), 6.95(2H, d, J 8.6 Hz), 7.17 (2H, d, J 8.6 Hz) and 8.56 (1H, s); m/z (ESP+)398 (MH⁺).

EXAMPLE 246-Dimethylamino-5-(4-Methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one

This compound was prepared as for Example 23 replacing morpholine withdimethylamine in Step 4. δ_(H) (250 MHz; CDCl₃); 2.47 (3H, s), 2.59 (6H,s), 3.70 (3H, s), 3.85 (3H, s), 6.91 (1H, s), 6.94 (2H, d, J8.7 Hz),7.17 (2H, d, J 8.7 Hz) and 8.50 (1H, s); m/z (ESP+) 356 (MH⁺).

EXAMPLE 251-Methyl-3-(4-methylthiazol-2-yl)-6-(4-morpholino)-1H-5-(4-pyridinyl)pyridin-2-one

Step 1: Methyl-4-pyridinylacetate (6.3 g) was dissolved inN,N-dimethylformamide (30 cm³) treated with N,N-dimethylformamidedimethyl acetal (15 cm³) and heated at 80° C. for 2 h. The reaction wasthen cooled and evaporated under high vacuum to afford crudemethyl-3-dimethylamino-2-(pyridin-4-yl)propenoate (7.3 g) which was usedwithout further purification.

Step 2:6-Hydroxy-1-methyl-3-(4-methylthiazol-2-yl)-1H-5-(4-pyridinyl)pyridin-2-onewas prepared as in Example 17 Step 2 replacingmethyl-3-dimethylamino-2-(4-methoxyphenyl)propenoate withmethyl-3-dimethylamino-2-(pyridin-4-yl)propenoate. δ_(H) (250 MHz;d6-DMSO); 2.76 (3H, s), 3.54 (3H, s), 7.40 (1H, s), 8.85 (2H, d, J 6.9Hz), 8.93 (2H, d, J 6.9 Hz) and 9.51 (1H, s); m/z (ESP+) 300 (MH⁺).

Step 3:6-Chloro-1-methyl-3-(4-methylthiazol-2-yl)-1H-5-(4-pyridinyl)pyridin-2-onewas prepared as in Example 17 Step 3 replacing6-hydroxy-5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-onewith6-hydroxy-1-methyl-3-(4-methylthiazol-2-yl)-1H-5-(4-pyridinyl)pyridin-2-one.δ_(H) (250 MHz; d6-DMSO); 2.4 (3H, s), 3.94 (3H, s), 7.37 (1H, s), 7.64(2H, d, J6.1 Hz), 8.31 (1H, s) and 8.72 (2H, d, J6.9 Hz); m/z (ESP+) 318and 320 (MH⁺).

Step 4:1-Methyl-3-(4-methylthiazol-2-yl)-6-(4-morpholino)-1H-5-(4-pyridinyl)pyridin-2-onecompound was prepared as for Example 17 Step 4 replacing6-chloro-5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-onewith6-chloro-1-methyl-3-(4-methylthiazol-2-yl)-1H-5-(4-pyridinyl)pyridin-2-one.δ_(H) (250 MHz; CDCl₃); 2.48 (3H, s), 2.86 (4H, m), 3.72 (4H, m), 3.79(3H, s), 6.96 (1H, s), 7.24 (2H, m), 8.41 (1H, s) and 8.72 (2H, m); m/z(ESP+) 369 (MH⁺).

EXAMPLE 261-Methyl-3-(4-methylthiazol-2-yl)-6-(1-pyrrolidino)-1H-5-(4-1pyridinyl)pyridin-2-one

The titled compound was prepared as for Example 25 replacing morpholinewith pyrrolidine in Step 4. δ_(H) (250 MHz; CDCl₃); 1.83-1.88 (4H, m),2.48 (3H, d, J 0.5Hz), 3.07 (4H, t, J 6.6Hz), 3.66 (3H, s), 6.93 (1H d,J 0.7 Hz), 7.22 (2H, dd, J 1.6 and 3.7 Hz), 8.44 (1H, s) and 8.68 (2H, J1.6 and 3.7 Hz); m/z (ESP+) 353 (MH⁺).

The following Examples have also been prepared in an analogous manner tothe preceding Examples.

Ex Z Y X R 27

Me 28

Me 29

Me 30

Me 31

Me 32

Me 33

Me 34

Me 35

Me 36

Me 37

H

Me 38

Me 39

Me 40

Me 41

Me 42

Me 43

Me 44

Et 45

Me 46

Me 47

Me 48

Me 49

Me 50

Me 51

Me 52

Me 53

HOCH₂CH₂— 54

Me 55

Me 56

Me 57

Me 58

Me 59

Me 60

Me 61

HOCH₂CH₂— 62

FCH₂CH₂— 63

Me 64

H 65

Me 66

Me 67

Me 68

Me 69

Me 70

Me 71

Me 72

Me 73

Me 74

Me 75

Me 76

Me 77

Me 78

Me 79

Me 80

Me 81

CH₂═CHCH₂— 82

Me 83

Me 84

Me 85

Me 86

Me 87

Me 88

Me 89

Me 90 Cl

Me 91

Me 92

Me 93

Me 94

Me 95

Me 96

Me 97

Me 98

Me 99

Me 100 

Me 101 

Me 102  MeNH—

Me 103 

Me 104 

Me 105 

Me 106 

Me 107 

Me 108 

Me 109 

Me 110 

Me 111 

Me 112 

Me 113 

Me 114 

Me 115 

Me 116 

Me 117 

Me 118 

Me 119 

Me 120 

Me 121 

Me 122  MeS—

Me 123  HOCH₂CH₂NH—

Me 124 

Me 125 

Me 126  MeNH—

Me 127 

Me 128 

Me 129 

Me 130 

Me 131 

Me 132  Me₂N—

Me 133  Me₂N—

Me 134 

Me 135 

Me 136 

Me 137 

Me 138 

Me 139 

Me 140 

Me 141 

Me 142  MeNH—

CH₂═CHCH₂— 143 

Me 144 

Me 145 

Me 146  H₂N—

Me 147 

Me 148 

Me 149 

Me 150 

Me 151 

Me 152  MeNH—

nPr 153 

Me 154 

Me 155 

Me 156 

Me 157 

Me 158 

Me 159 

Me

What is claimed is:
 1. A compound which is a derivative of formula I ora salt thereof:

wherein: R is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₂₋₆alkenyloxy or C₂₋₆alkynyloxy, and when R is not hydrogen, R isoptionally independently substituted by one or more halogen atoms orhydroxy group; V is CH; W is O; X is a five-membered heteroaromaticgroup containing one, two, three or four heteroatoms independentlyselected from N, O and S providing that not more than one heteroatom isselected from O and S, the heteroaromatic group being unsubstituted orsubstituted with one or more groups independently selected from halogen,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, C₄₋₆cycloalkenyland CF₃; Y is hydrogen, NR¹R², C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, Ar,O(CH₂)_(n)Ar¹, or C_(k)H_(2k−4)Ar²; R¹ and R² are independently selectedfrom C₁₋₆alkyl and (CH₂)_(m)Ar³; Ar is thienyl, furyl or a six-memberedheteroaromatic ring containing one or two nitrogen atoms which isunsubstituted or substituted with one or more groups independentlyselected from halogen and C₁₋₆alkyl groups and which is optionally fusedto a benzene ring; or napththyl or phenyl rings which rings areunsubstituted or substituted with one or more groups independentlyselected from halogen, cyano, amino, nitro, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, CF₃, CF₃O, C₁₋₆alkoxy, C₂₋₆alkenyloxy, C₂₋₆alkynyloxy,C₁₋₆alkylthio, C₂₋₆alkenylthio C₂₋₆alkynylthio, hydroxy,hydroxyC₁₋₆alkyl, NR³R⁴, OC(O)NR³R⁴, C₁₋₆alkoxyphenylC₁₋₆alkoxy,cyanoC₁₋₆alkyl, cyanoC₂₋₆alkenyl, cyanoC₂₋₆alkynyl, pyridyl, phenyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl,C₁₋₆alkoxycarbonylC₂₋₆alkenyl, C₁₋₆alkoxycarbonylC₂₋₆alkynyl and—O(CH₂)_(p)O— and which is optionally fused to a benzene ring; Ar¹, Ar²,Ar³ are independently selected from pyridyl; and phenyl which isunsubstituted or substituted with one or more groups independentlyselected from halogen, cyano, amino, nitro, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, CF₃, C₁₋₆alkoxy, C₂₋₆alkenyloxy, C₂₋₆alkynyloxy,C₁₋₆alkylthio, C₂₋₆alkenylthio, C₂₋₆alkynylthio and —O(CH₂)_(p)O—; Z isHet¹; R³, and R⁴ are independently hydrogen or C₁₋₆alkyl; R⁵ and R⁶ areindependently selected from hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆hydroxyalkyl and (CH₂)_(m)Ar³; Ar⁴ is phenyl which isunsubstituted or substituted with one or more groups independentlyselected from halogen, cyano, amino, nitro, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, CF₃, C₁₋₆alkoxy, C₂₋₆alkenyloxy, C₂₋₆alkynyloxy,C₁₋₆alkylthio, C₂₋₆alkenylthio, C₂₋₆alkynylthio and —O(CH₂)_(p)O—; Het¹is a four- or five-membered saturated ring containing a nitrogen atomoptionally substituted by a hydroxy group; a six-membered saturated ringcontaining a nitrogen atom, and optionally a further nitrogen atom or anoxygen atom; an unsaturated five-membered heterocyclic group containingone, two, three or four heteroatoms independently selected from N, O andS providing that not more than one heteroatom is selected from O and S;or an unsaturated six-membered heterocyclic group containing one or twonitrogen atoms; each of which moieties is unsubstituted or substitutedby one or more groups independently selected from halogen, cyano, amino,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, CF₃, C₁₋₆alkoxy, C₂₋₆alkenyloxy,C₂₋₆alkynyloxy; k is 2; m and n are 1; and p is 1, or
 2. 2. A compoundaccording to claim 1 wherein: R is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy or C₂₋₆ alkynyloxy; V is CH;and W is O.
 3. A compound according to claim 1, wherein: Y is hydrogen,NR¹R², C₂₋₆ alkynyl, Ar, O(CH₂)_(n)Ar¹ or C_(k)H_(2k−4)Ar²; R¹ and R²are independently selected from C₁₋₆ alkyl and (CH₂)_(m)Ar³; Ar ispyridyl or pyrimidinyl and is unsubstituted or substituted with halogenor C₁₋₆ alkyl; unsubstituted naphthyl; or phenyl which is unsubstitutedor substituted with R^(x) and/or R^(y) and/or R^(z) wherein R^(x) andR^(y) are independently chosen from halogen, cyano, amino, nitro, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, CF₃, OCF₃, C₁₋₆ alkoxy, C₂₋₆alkenyloxy, C₂₋₆ alkynyloxy, C₁₋₆ alkylthio, C₂₋₆ alkenylthio, C₂₋₆alkynylthio, hydroxy, hydroxyC₁₋₆alkyl, NR³R⁴, OC(O)NR³R⁴, C₁₋₆alkoxyphenylC₁₋₆alkoxy, cyanoC₁₋₆alkly, cyanoC₂₋₆alkenyl,cyanoC₂₋₆alkynyl, pyridyl, phenyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkoxycarbonylC₁₋₆alkyl, C₁₋₆ alkoxycarbonylC₂₋₆alkenyl, C₁₋₆alkoxycarbonylC₂₋₆alkynyl and —O(CH₂)_(p)O— and R^(z) is halogen, C₁₋₆alkyl or C₁₋₆ alkoxy and Ar is optionally fused to a benzene ring; Ar¹,Ar² and A³ are independently: pyridyl; or phenyl which is unsubstitutedor substituted with halogen, cyano, amino, nitro, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, CF₃, C₁₋₆ alkoxy, C₂₋₆ alkenyloxy, C₂₋₆alkynyloxy, C₁₋₆ alkythio, C₂₋₆ alkenylthio, C₂₋₆ alkynylthio or—O(CH₂)_(p)O—; R³ and R⁴ are independently chosen from hydrogen andC₂₋₆alkyl; k is 2; m and n are 1; and p is 1 or
 2. 4. A compoundaccording to claim 1 which is:3-(4-methoxyphenyl)-1-methyl-5-(thiazol-2-yl)-1H-[2,4′]bipyridinyl-6-one;5-(4-methoxyphenyl)-1-methyl-6-(5-methylfuran-2-yl)-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-1H-pyridin-2-one;3-(4-methoxyphenyl)-1-methyl-5-(4-methylthiazol-2-yl)-1H-[2,4′]bipyridinyl-6-one;5-(4-methoxyphenyl)-1-methyl-3-(thiazol-2-yl)-6-(3-thienyl)-1H-pyridin-2-one;5-(4-methoxyphenyl)-1-methyl-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-6-(3-thienyl)-1H-pyridin-2-one;5-(4-methoxyphenyl)-1-methyl-6-(5-methylfuran-2-yl)-3-(thiazol-2-yl)-1H-pyridin-2-one;3-(4-methoxyphenyl)-1-methyl-5-(thiophen-2-yl)-1H-[2,4′]bipyridinyl-6-one;3-(4-methoxyphenyl)-1-methyl-5-(4-cyclopropylthiazol-2-yl)-1H-[2,4′]bipyridinyl-6-one;1-methyl-3-(4-pyridyl)-5-(thiazol-2-yl)-1H-[2,4′]bipyridinyl-6-one;3-(4-methoxyphenyl)-1-methyl-5-(4-methylthiophen-2-yl)-1H-[2,4′]bipyridinyl-6-one;5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-pyridazin-4-yl-1H-pyridin-2-one;1-methyl-3-(4-methylthiazol-2-yl)-6-(pyridazin-4-yl)-5-(2,4,6-trifluorophenyl)-1H-pyridin-2-one;5-benzyloxy-1-methyl-3-(4-methylthiazol-2-yl)-6-(pyridin-4-yl)-1H-pyridin-2-one;1-methyl-3-(1-methylpyrazol-3-yl)-5-(4-methoxyphenyl)-6-(pyridin-4-yl)-1H-pyridin-2-one;5-(3,4-methylenedioxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-(pyridin-4-yl)-1H-pyridin-2-one;5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-(pyrazin-2-yl)-1H-pyridin-2-one;5-(4-methoxyphenyl)-3-(3-methylisothiazol-5-yl)-6-(4-pyridyl)-1-methyl-1H-pyridin-2-one;1-methyl-3-(4-methylthiazol-2-yl)-5-(N-methyl-N-benzylamino)-6-(4-pyridyl)-1H-pyridin-2-one;5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-(4-morpholino)-1H-pyridin-2-one;1-methyl-3-(4-methylthiazol-2-yl)-6-(4-morpholino)-1H-[3,4′]bipyridin-2-one;1-methyl-3-(4-methylthiazol-2-yl)-6-(1-pyrrolidino)-1H-[3,4,′]bipyridin-2-one;or a salt thereof.
 5. A pharmaceutical composition comprising a compoundaccording to claim 1, or a salt thereof, and a pharmaceuticallyacceptable carrier.
 6. A compound according to claim 1, or a saltthereof, for use in a method of treatment of the human or animal body.7. Use of a compound according to claim 1, or a salt thereof, for themanufacture of a medicament for the treatment of disorders for which theadministration of a ligand for the GABA_(A) receptor α2 and/or α3subunits is required.
 8. A prophylactic or therapeutic method oftreatment of a subject suffering from a condition for which theadministration of a ligand for the GABA_(A) receptor α2 and/or α3subunit is required, which comprises administering to that subject aprophylactically or therapeutically effective amount of a compoundaccording to claim 1, or a salt thereof.
 9. A process for producing acompound according to claim 1 in which V is CH which comprises: reactinga compound of formula VII with a compound of formula

 wherein R, X, Y and Z are as defined in claim 1 and R″ and R′″ areindependently halogen or C₁₋₆ alkyl.